Aging – the program

Yuri Deigin, Geektimes

"The strongest survives" – sometimes pathetically declare all sorts of "masters of life", distorting the original meaning of Darwin's thought.

"The fittest survives," Darwin meant, evolutionary biologists explain to us.

Adapted to what? To maximum reproduction in the current conditions. Who is this "adapted"? An individual or a rabbit? No, of course not. The individual will not survive anyway. The collective of genes that created the most "adapted" rabbit survives. One that will outstrip fellow humans in ensuring their genes maximum survival by creating as many copies of them as possible.

And what is "maximum survival"? By what parameter will we maximize? "This is already to your taste," Game Theory tells us. Do you want a local maximum of your copies at a particular time? Get it, sign it. Just don't complain that ah, how happiness is fleeting, after you die out from exhaustion of resources.

Do you want to live happily ever after? That is, maximize the area under the curve of your copies in time? Then be kind enough to learn how to control the consumption of resources by your replicators, or at least give them skills to wait out long periods of adverse conditions. And better both.

But the most chic thing is to grow their intelligence so that they themselves begin to control their population for you, plan the consumption of their resources, and even come up with more and more effective ways to extract these resources. Such replicators can breed as many as 7.5 billion of your gene cooperatives of 30-40 trillion copies in each cell of the human body. For bacteria, of course, these are ridiculous figures, but for eukaryotes it is quite an indicator.

True, it takes a long time to grow intelligence, and there is a chance not to grow it, Neanderthals tell us. It's like this: if you, as a young, daring startup cooperative, decide to encode the ability to think in your replicators using the "trillion macaques on typewriters" method, then until your code is ready for production release, you have to control the population of these beta replicators yourself. And then another subroutine called fruit_and_ multiply is trying to send all your efforts to /dev/null. Therefore, the cooperative "Genes and Sons" had to first hone the ability not to let their creatures die out or multiply greatly. To do this, he first coded mechanisms for controlling the inflow and outflow of the population. Having learned to control the influx of individuals through the shutdown of reproduction, and the outflow through phenoptosis is either sharp like a salmon, or smooth, like we have with a mouse.

Is death programmed in Pacific salmon? I think almost anyone who is in the topic will admit that yes. But there is a heated debate about whether it is programmed in our country.

This is a terrible word – "program"

What distinguishes a program from a non-program? Everything is very simple here. A program is when changes happen on purpose. Non–program - when stochastically, randomly.

After all, no one claims that embryogenesis is accidental. Or that puberty is a stochastic process. No, everything is clearly programmed: stages, deadlines. And that is why we do not observe single sexually mature infants or 80-year-old women in labor, as they should have been if these were random processes. And if the nature of aging is accidental, then why do some animal species live for several days, while others live for hundreds of years? After all, similar random processes are characterized by similar statistical distributions of their results. But for some reason, the parameters of these distributions vary greatly even for such close relatives as a mouse (2-3 years of life), a squirrel (10-12 years) and a naked digger (30 years):

Moreover, in social animals, the life span may differ by an order of magnitude even in twins with identical DNA. The uterus lives 20-40 times longer than the working individual.

Along with this, we know that very different species have common molecular mechanisms of aging. Both worms and mammals have, for example, the notorious cascade of insulin–like growth factor (IGF-1), which first helps the body to mature and then die. At the same time, the aging rates are very different: the nematode lives for 2-3 weeks, and the mouse lives for 2-3 years. And this also does not fit well with the hypothesis of the random nature of age-related changes.

At the same time, all gerontologists agree that our body's ability to repair damage and clean up debris decreases with age. And that it is this decline that leads to the accumulation of both, and ultimately to death – that is, everyone agrees that this process of degradation is the main cause of our aging.

The only stumbling block is whether this age–related decline is accidental or purposeful? It seems to me that all the data indicate that the role of randomness in this process is minimal. We see how the body purposefully destroys our thymus from the age of 15, our brain from 25, our muscles from 45, and our bones from 60. And the same processes, only accelerated by 20-30 times, we observe even in mice. And it is very difficult to believe that they are all random.

Where are the aging genes? Who manages this process?

I have already written about the main mechanism of control and synchronization of important processes in the body – epigenetics. With age, it changes the same for everyone – the "epigenetic clock" perfectly predicts our biological age, and the fact that the periodic rollback of these epigenetic clocks by Yamanaki factors prolonged the life of mice confirms this hypothesis for me.

Who sets the rhythm for this clock and drives it forward? Most likely, our brain. Or rather, the hypothalamus with the pituitary gland, based on circadian rhythms from the pineal gland. Here is an interesting study showing how stress through corticosteroid hormones causes epigenetic changes in 5-year-olds, similar to those that we see with normal aging. Who produces cortisol? The hypothalamus-pituitary-adrenal axis. And the above study well confirms the role of epigenetics in the implementation of the aging program – stress accelerates it, Yamanaki factors roll back.

Moreover, we see how similar these processes are in all organisms. Nematodes also have a primitive neuroendocrine system – in fact, the rudiments of the hypothalamus-pituitary-gonad axis. And it is this axis that controls their growth and development. When there is a shortage of food, it turns on the non–aging mode - the dower stage, in which the nematode can stay for months, and then it turns on the growth process again, and the worm matures, multiplies and dies in its standard few weeks.

By the way, do you remember the aforementioned cascade of insulin-like growth factor (IGF-1)? This is also one of the genes of aging. In nematodes, it is called daf-2. His knockout (removal) extended the life of nematodes by 10 times, and mice - by 2. And this cascade is very evolutionarily old, just superstar (sorry) – it exists in yeast, nematodes, and us.

At the same time, of course, we still do not fully understand all the mechanisms of these processes. If (or rather, when) we understand, then all the debates about the nature of aging will be resolved. To the question "where is the program" there will be an unambiguous answer: here it is, the genes are such and such, the mechanisms of their control are such and such, the introductory parameters are such and such, the algorithm is such and such.

How to test the hypothesis of programmed aging?

I have a very simple and applied approach here: if the hypothesis of the aging program allows us to stop this aging or at least prolong our life 10 times, this will be more than enough for me. So far, no other hypotheses have found means of prolonging life better than starvation, and for primates it is ineffective.

Another hypothesis: if aging is a program, it must have some key mechanisms that vary the main parameter of the program – life expectancy. By influencing these mechanisms, we should see the impact on the outcome of the program. This is what the results of life extension at times demonstrate to us with the help of knockout of development/aging genes on nematodes and mice.

How has evolution honed the mechanisms of aging?

I don't know, I didn't hold a candle. I will only make a cautious assumption that billions of years ago, aging most likely did not exist. As it is not observed, for example, in viruses. But at some point it arose in unicellular organisms and gave them an advantage in survival by preventing their extinction due to overpopulation (or in some other ways). We know two such mechanisms of aging in unicellular cells – apoptosis and telomeres. Moreover, these mechanisms perfectly show the effect of group selection – for each individual cell, limiting its division or self-destruction clearly does not help to fulfill the task of reproduction. But it helps their genes a lot.

When multicellular ones arose, the war between individual-level selection and group selection took a new turn. Group selection encouraged new and new mechanisms of aging, and individual selection tried to crack them.

And for hundreds of millions of years, those species that did not have strong enough protection mechanisms against hacking bypassed their aging program, fixed the genes of this hacking in their population due to the selection pressure at the individual level, which, of course, is stronger than the group selection pressure (since the reproductive advantage of an individual from prolonging life is realized much more faster than the onset of the negative consequences of this benefit for the entire population). But in the end, these species, when this advantage was already fixed in the genes of a sufficiently large number of individuals, died out due to hunger caused by overpopulation, from which such a species suffered at least once during millions of years of evolution. And only those species escaped extinction in which group selection secured a sufficient number of duplicating aging mechanisms, and those that learned to wait out the "hungry times" in the form of spores or "hidden eggs" as an ageless hydra.

By the way, the multidirectional action (antagonistic pleiotropy) of IGF1 is exactly the mechanism that allows the aging program to remain in the population. Moreover, the mechanism is very tricky, because this gene gives an evolutionary advantage to individuals in the early stages of development – rapid growth – which fixes it in the population, in exchange for the fact that these rapidly reproducing individuals remain mortal.

At the same time, such a multidirectional IGF-1 is not some kind of inevitability and is not caused by any physical law. Evolution could do very well without it if it did not have the task of preventing overpopulation. After all, the coupling of rapid growth with aging imposes obvious restrictions on the fertility of each individual. And those individuals who could break this coupling would receive a clear evolutionary advantage in reproduction.

Surely evolution would not be able to untie puberty genes from their negative manifestations in the form of thymus involution and other manifestations of aging over billions of years? After all, she was able to invent stunning things – first to make multicellular ones out of unicellular ones, then to drive fish onto land, teaching them to breathe air, and then to teach some to fly. She was able to create huge dinosaurs and whales, as well as many other absolutely fantastic life forms and ecosystems. But at the same time, the vast majority of her creatures have the same coupling between the genes of puberty and aging: even in nematodes, even in humans. It is much more plausible that evolution actively "did not want" to break this coupling, and not "could not".

And yes, in the vast majority of species, but not all. There are species that do not have a direct relationship between fertility (and this is the main criterion for the effectiveness of developmental genes) and aging. Someone's fertility only increases with age:

Where is the paleontological evidence of extinct immortal species?

And what could such paleontological evidence look like? How to distinguish the fossilized remains of an immortal organism from a mortal one? Moreover, aging most likely arose in unicellular cells, as we see in yeast. And, by the way, unicellular aging is indirect paleontological evidence.

Well, as a hypothesis: 252 million years ago, about 90% of all species died out on earth. One of the possible causes of this catastrophe is the explosive growth of bacteria that destroyed one of the basic links in the ecological pyramid. After all, with the extinction of an entire link of the ecological pyramid, everything above this link in the pyramid is also at risk of dying out. And there have been several such catastrophes on Earth:

Couldn't evolution just invent an immortal species that doesn't cause overpopulation?

First of all, the driver of evolution is still genes, and they, roughly speaking, do not care whether we multiply them or our descendants. At the same time, the ways of evolution are inscrutable – it could have gone this way, it could have gone that way. Could we be able to fly and breathe nitrogen? Maybe they could. But it turned out well enough.

By the way, evolution may have already been able to invent such an "immortal" species – this is the hydra beloved by gerontologists, which does not age. But for this she had to learn cryptobiosis (to wait out the hungry times), as well as to reproduce both sexually and by budding. When there is a lot of food, hydra clones itself by budding. And when it's not enough, she grows either male or female genitals for herself, and makes love, leaving the fertilized eggs to wait for better times at the bottom of the ocean. That's how she learned to wait out unfavorable conditions – parents can die of hunger, but children will wait out hunger, since their development is frozen until better times come. Just like a dower nematode larva.

And another species on the threshold of immortality is us, Homo Sapiens. Just to learn not to die out from overpopulation, we had to first grow our brains, and then with their help come up with a culture and society, and even scientific and technological progress, which will provide us with the technical capabilities not to die from resource depletion in any population. I have no doubt that we will break this stupid aging program. A matter of time.

And I would really like it to happen not in 50 years, but in 20. But something a reasonable Person does not yet understand that in this matter procrastination is like death.

Portal "Eternal youth" http://vechnayamolodost.ru  07.07.2017